02-8 Envenomation

8 Envenomation

Envenomation J White Comprehensive evaluation of the envenomed patient 152 Geographical distribution of venomous snakes 153 Bedside tests in the envenomed patient 153 Overview of envenomation 154 Venom 154 Venomous animals 154 Clinical effects 155 General approach to the envenomed patient 156 First aid 156 Assessment and management in hospital 158 Treatment 159 Follow-up 160 Envenomation by specific animals 160 Venomous snakes 160 Scorpions 161 Spiders 161 Paralysis ticks 161 Venomous insects 161 Marine venomous and poisonous animals 162

152 • ENVENOMATION Comprehensive evaluation of the envenomed patient Copyright © Julian White. Cranial nerves Drooling Dysarthria Dysphagia Upper airway compromise Mouth, gums Evidence of bleeding Increased salivation Drooling Chest Pulmonary oedema Diminished respiration Bite/sting site Pain Swelling Bruising Discoloration Necrosis Skin In addition to (6): Piloerection Erythema Blistering Infection Level of consciousness Confusion Agitation Seizures Eyes Miosis or mydriasis Increased lacrimation Corneal injury (venom spit injury) Airway, breathing, circulation Blood pressure Pulse Respiration rate Oxygen saturation Dysrhythmias Bilateral mild ptosis Ptosis and lateral ophthalmoplegia Fixed dilated pupils Chemosis – can indicate capillary leak syndrome Local increased sweating

Local bleeding, blistering Local bleeding

Muscles Weakness Tenderness Pain

Lymph nodes Tender or enlarged nodes draining bite/sting area

Abdomen Intra-abdominal, retroperitoneal or renal pathology

Reflexes Decreased or absent reflexes

Bedside tests in the envenomed patient • 153

Geographical distribution of venomous snakes The geographical location of a snakebite determines the likely animal(s) involved and the nature and risks of the envenomation. Copyright © Julian White. South American rattlesnake Crotalus durissus Indian krait Bungarus caeruleus European adder Vipera aspis Green pit viper Trimeresurus gramineus Russell’s viper Daboia russelii Black-necked spitting cobra Naja nigricollis Monacled cobra Naja kaouthia Common Indian cobra Naja naja Puff adder Bitis arietans Saw-scaled viper Echis carinatus Examination of urine. Haematuria may indicate a coagulopathy. Dark urine is suggestive of myoglobinuria, which is a sign of extensive rhabdomyolysis. Copyright © Julian White. Bedside tests in the envenomed patient Twenty-minute whole-blood clotting test (20WBCT). The presence of coagulopathy is a key indicator of major envenoming for some species. While full laboratory coagulation studies may be the ideal, the 20WBCT has emerged as a simple standardised bedside test of coagulopathy, applicable even in areas with limited health facilities. Copyright © Julian White. 1 Obtain a clean glass container (test tube or bottle) that is either new, or has only been washed with water (not detergent/soap) 2 Place 2–3 mL venous blood in the glass container 3 Allow to stand undisturbed for 20 mins 4 Gently invert/tip the glass container checking for presence of a blood clot 4a Clot present = negative test (no coagulopathy present) 4b Clot absent = positive test (coagulopathy present)

4a 4b

154 • ENVENOMATION Venomous animals There are many animal groups that contain venomous species (Box 8.2). The epidemiological estimates reflect the importance of snakes and scorpions as causes of severe or lethal envenomation, but also the fragmentary nature of the data. For snakes, recent studies have proposed widely varying estimates of epidemiological impact, but even the higher estimates may be too low. A recent Overview of envenomation Envenomation occurs when a venomous animal injects sufficient venom by a bite or a sting into a prey item or perceived predator to cause deleterious local and/or systemic effects. This is defined as a venom-induced disease (VID). Venomous animals generally use their venom to acquire and, in some cases, pre-digest prey, with defensive use a secondary function for many species. Accidental encounters between venomous animals and humans are frequent, particularly in the rural tropics, where millions of cases of venomous bites and stings occur annually. Globally, an increasing number of exotic venomous animals are kept privately, so cases of envenoming may present to hospitals where doctors have insufficient knowledge to manage potentially complex presentations. Doctors everywhere should thus be aware of the basic principles of management of envenomation and how to seek expert support. It is important for doctors to know what types of venomous animal are likely to occur in their geographical area (hospital hinterland; p. 153) and the types of envenoming they may cause. Venom Venom is a complex mixture of diverse components (notably toxins), often with several separate toxins that can cause adverse effects in humans, and each is potentially capable of multiple effects (Box 8.1). Venom is produced at considerable metabolic cost, so is used sparingly; thus only some bites/ stings by venomous animals result in significant envenoming, the remainder being ‘dry bites’. The concept of dry bites is important in understanding approaches to first aid and medical management. 8.2 Venomous animals and human envenoming Phyla Principal venomous animal groups Estimated number of human cases/year Estimated number of human deaths/year Chordata Snakes

2.5 million 100 000 Spiny fish ? > 100 000 Close to zero Stingrays ? > 100 000 ? < 10 Arthropoda Scorpions 1 million ? < 5000 Spiders ? > 100 000 ? < 100 Paralysis ticks ? > 1000 ? < 10 Insects ? > 1 million ? > 1000* Mollusca Cone snails ? < 1000 ? < 10 Blue-ringed octopus ? < 100 ? < 10 Coelenterata Jellyfish ? > 1 million ? < 10 *Social insect stings cause death by anaphylaxis rather than primary venom toxicity, except for massive multiple sting attacks. Copyright © Julian White. Copyright © Julian White. All venom components have lethal potential. 8.1 Key venom effects Venom component Clinical effects Type of venomous animal Neurotoxin Paralytic Flaccid paralysis Some snakes Paralysis ticks Cone snails Blue-ringed octopus Excitatory Neuroexcitation: autonomic storm, cardiotoxicity, pulmonary oedema Some scorpions, spiders, jellyfish (irukandji) Myotoxins Systemic or local myolysis Some snakes Cardiotoxins Direct or indirect cardiotoxicity; cardiac collapse, shock Some snakes, scorpions, spiders and jellyfish (box jellyfish) Haemostasis system toxins Variation from rapid coagulopathy and bleeding to thrombosis, deep venous thrombosis and pulmonary emboli Many snakes and a few scorpions (Hemiscorpius) Brazilian caterpillars (Lonomia) Haemorrhagic toxins Local vessel damage, fluid extravasation, blistering, ecchymosis, shock Mainly some snakes Nephrotoxins Renal damage Some snakes, massed bee and wasp stings Necrotoxins Local tissue injury/necrosis, shock Some snakes, a few scorpions (Hemiscorpius), spiders (recluse spiders), jellyfish and stingrays Allergic toxins Induction of acute allergic response (direct and indirect) Almost all venoms but particularly those of social insects (i.e. bees, wasps, ants)

Overview of envenomation • 155

local effects predominate over systemic, and for some, such as certain snakes, both are important (p. 152). Some species commonly cause local necrosis, notably some snakes, brown recluse spiders, an Iranian scorpion (Hemiscorpius lepturus) and some stingrays. General systemic effects By definition, these are non-specific (Box 8.3). Shock is an important complication of major local envenoming by some snake species and, if inadequately treated, can prove lethal, especially in children. Specific systemic effects These are important in both diagnosis and treatment. • Neurotoxic flaccid paralysis can develop very rapidly, progressing from mild weakness to full respiratory paralysis in less than 30 minutes (blue-ringed octopus bite, cone snail sting), or may develop far more slowly, over hours (some snakes) to days (paralysis tick). For neurotoxic snakes, the cranial nerves are usually involved first, with ptosis a common initial sign, often progressing to partial and later complete ophthalmoplegia, fixed dilated pupils, drooling and loss of upper airway protection (p. 152). From this, paralysis may extend to the limbs, with weakness and loss of deep tendon reflexes, the neck (‘broken neck’ sign), then finally respiratory paralysis affecting the diaphragm. • Excitatory neurotoxins cause an ‘autonomic storm’, often with profuse sweating (p. 152), variable cardiac effects and cardiac failure, sometimes with pulmonary oedema (notably, Australian funnel web spider bite, some scorpions such as Indian red scorpion). This type of envenomation can be rapidly fatal (many scorpions, funnel web spiders), or may cause distressing symptoms but constitute a lesser risk of death (widow spiders, banana spiders). • Myotoxicity can be localised in the bitten limb, or systemic, affecting mostly skeletal muscles. It can initially be silent, then present with generalised muscle pain, tenderness, myoglobinuria (p. 153) and huge rises in serum creatine kinase (CK). Secondary renal failure can precipitate potentially lethal hyperkalaemic cardiotoxicity. • Cardiotoxicity is often secondary but symptoms and signs are non-specific in most cases. For some scorpions, envenomation can cause direct cardiac effects, including decreased cardiac output, arrhythmias and pulmonary oedema. • Haemostasis system toxins cause a variety of effects, depending on the type of toxin (Fig. 8.1). Coagulopathy may present as bruising and bleeding from the bite site (p. 152), gums and intravenous sites. Surgical interventions are high-risk in such cases. Other venoms cause thrombosis, usually presenting as deep venous thrombosis (DVT), pulmonary embolus or stroke (particularly Caribbean/Martinique vipers). • Haemorrhagic toxins cause vascular damage, especially in the bitten limb, with extravasation of fluid and sometimes hypotensive shock; this is a problem associated with some snakebites. The role of these toxins in causing latedeveloping capillary leak syndrome (p. 152), again comprehensive study in India indicated there are at least 45 000 snakebite-related deaths in that country annually, far above both government figures and previous estimates. In many areas of the poor rural tropics, health resources are limited and few envenoming cases are either seen or recorded within the official hospital system, compared to the actual community burden of disease. While fatal cases may gain most attention, long-term disability from envenomation affects significantly more people and has a major social and economic cost. Stings by social insects such as bees and wasps may also cause lethal anaphylaxis. Other venomous animals may commonly envenom humans but cause mostly non-lethal effects. A few animals only rarely envenom humans but have a high potential for severe or lethal envenoming. These include box jellyfish, cone snails, blue-ringed octopus, paralysis ticks and Australian funnel web spiders. Within any given group, particularly snakes, there may be a wide range of clinical presentations. Some are described here but for a more detailed discussion of the types of venomous animal, their venoms and their effects on humans, see toxinology.com. Clinical effects With the exception of dry bites, where no significant toxin effects occur, venomous bites/stings can result in three broad classes of effect. Local effects These vary from trivial to severe (Box 8.3). There may be minimal or no local effects with some snakebites (not even pain), yet lethal systemic envenoming may still be present. For other species, Copyright © Julian White. 8.3 Local and systemic effects of envenomation Local effects • Pain • Sweating • Erythema • Major direct tissue trauma (e.g. stingray injuries) • Blistering • Necrosis • Swelling • Bleeding and bruising Non-specific systemic effects • Headache • Nausea • Vomiting and diarrhoea • Abdominal pain • Tachycardia or bradycardia • Hypertension or hypotension • Pulmonary oedema • Dizziness • Collapse • Convulsions • Shock • Cardiac arrest Specific systemic effects • Neurotoxic flaccid paralysis (descending or ascending) • Excitatory neurotoxicity (catecholamine storm-like and similar) • Rhabdomyolysis (systemic or local) • Coagulopathy (procoagulant/fibrinolytic or anticoagulant or thrombotic or antiplatelet) • Cardiotoxicity (decreased/abnormal cardiac function or arrhythmia or arrest) • Acute kidney injury (polyuria or oliguria or anuria or isolated elevated creatinine/urea)

156 • ENVENOMATION General approach to the envenomed patient First aid First aid can be crucial in determining the outcome for envenomed patients, yet throughout much of the world inappropriate and dangerous first aid is often administered. associated with some snakebites (notably Russell’s viper), is uncertain. • Renal damage in envenoming is mostly secondary, although some species, such as Russell’s vipers, can cause primary renal damage. The presentation is similar in both cases, with changes in urine output (polyuria, oliguria or anuria) or rises in creatinine and urea. In cases with intravascular haemolysis, secondary renal damage is likely. The clinical effects of specific animals in different regions of the world are shown in Boxes 8.4–8.6. Fig. 8.1 Sites of action of venoms on the haemostasis system. Copyright © Julian White. Haemorrhagic metalloproteinases and disintegrins Damage blood vessel wall, cause leakage of blood, degrade platelet plug response Direct fibrinolytics Split fibrinogen, often abnormally, resulting in poor clot formation and a bleeding tendency Procoagulants Activate specific coagulation factors to activate clotting cascade and promote formation of fibrin clots. Can also activate fibrinolytic system, resulting in defibrination and reduced ability to form protective clots Other haemostasis system toxins Target various parts of haemostasis, either as activators (e.g. plasminogen activators), or as inhibitors of coagulation (e.g. serpin inactivators, platelet aggregation inhibitors) Clotting factor pathways Factor II Factor IIa Fibrinogen Fibrin

8.4 Selected important venomous animals in Asia Scientific name1 Common name Clinical effects Antivenom/antidote/treatment Indian subcontinent Bungarus spp. (E) Kraits Flaccid paralysis2,3, myolysis4, hyponatraemia5 Indian PV or specific Naja spp. (E) Cobras Flaccid paralysis3, local necrosis/blistering, shock Indian PV or specific Ophiophagus hannah (E) King cobra Flaccid paralysis3, local necrosis, shock Indian PV or specific Echis spp. (Vv) Saw-scaled vipers Procoagulant coagulopathy, local necrosis/blistering, renal failure Indian PV or specific Daboia russelii (Vv) Russell’s viper Procoagulant coagulopathy, local necrosis/blistering, myolysis, renal failure, shock, flaccid paralysis2 Indian PV or specific Hypnale spp. (Vc) Hump-nosed vipers Procoagulant coagulopathy, shock, renal failure Try Indian PV Trimeresurus6 spp. (Vc) Green pit vipers Procoagulant coagulopathy, local necrosis, shock Indian PV or specific Hottentotta spp. (Sc) Indian scorpions Neuroexcitation, cardiotoxicity Indian specific AV Prazosin East Asia Bungarus spp. (E) Kraits Flaccid paralysis2,3 Specific AV from country Naja spp. (E) Cobras (some spitters) Flaccid paralysis3, local necrosis/blistering, shock Specific AV from country Ophiophagus hannah (E) King cobra Flaccid paralysis3, local necrosis, shock King cobra AV Calloselasma rhodostoma (Vc) Malayan pit viper Procoagulant coagulopathy, local necrosis/blistering, renal failure, shock Specific AV from country Daboia siamensis (Vv) Russell’s viper Procoagulant coagulopathy, local necrosis/blistering, renal failure, shock Specific AV from country Gloydius spp. (Vc) Mamushis, pit vipers Procoagulant coagulopathy, local necrosis/blistering, shock, renal failure, flaccid paralysis2 Specific AV from country Trimeresurus6 spp. (Vc) Green pit vipers, habus Procoagulant coagulopathy, local necrosis/blistering, shock Specific AV from country 1Family names: C = ‘Colubridae’ (mostly ‘non-venomous’; family subject to major taxonomic revisions); E = Elapidae (all venomous); Sc = Scorpionoidea; Vc = Viperidae Crotalinae (New World and Asian vipers); Vv = Viperidae viperinae (Old World vipers). 2Pre-synaptic. 3Post-synaptic. 4Only reported so far for B. candidus, B. niger and B. caeruleus. 5Only reported so far for B. multicinctus and B. candidus. 6Genus is subject to major taxonomic change (split into at least eight genera). (AV = antivenom; PV = polyvalent) More information is available from WHO-SEARO Guidelines for the management of snake-bites and from toxinology.com. Copyright © Julian White.

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8.5 Selected important venomous animals in the Americas and Australia Scientific name1 Common name Clinical effects Antivenom/antidote/treatment North America Crotalus spp. (Vc) Rattlesnakes Procoagulant coagulopathy, local necrosis/ blistering (flaccid paralysis2 rare), shock CroFab AV or Bioclon Antivipmyn AV Sistrurus spp. (Vc) Massasaugas Procoagulant coagulopathy, local necrosis/ blistering, shock CroFab AV or Bioclon Antivipmyn AV Agkistrodon spp. (Vc) Copperheads and moccasins Procoagulant coagulopathy, local necrosis/ blistering, shock CroFab AV or Bioclon Antivipmyn AV Micrurus spp. (E) Coral snakes Flaccid paralysis3 Bioclon Coralmyn AV Latrodectus mactans Widow spider Neuroexcitation MSD Widow spider AV Centruroides sculpturatus Arizona bark scorpion Neuroexcitation Bioclon Anascorp AV Central and South America Crotalus spp. (Vc) Rattlesnakes Flaccid paralysis2, myolysis, procoagulant coagulopathy, shock, renal failure Specific AV from country Bothrops spp. (Vc) Lancehead vipers Procoagulant coagulopathy, local necrosis/ blistering, shock, renal failure Specific AV from country Bothriechis spp. (Vc) Eyelash pit vipers Shock, pain and swelling Specific AV from country Lachesis spp. (Vc) Bushmasters Procoagulant coagulopathy, shock, renal failure, local necrosis/blistering Specific AV from country Micrurus spp. (E) Coral snakes Flaccid paralysis2,3, myolysis, renal failure Specific AV from country Tityus serrulatus Brazilian scorpion Neuroexcitation, shock Instituto Butantan scorpion AV Loxosceles spp. Recluse spiders Local necrosis Instituto Butantan spider AV Phoneutria nigriventer Banana spider Neuroexcitation, shock Instituto Butantan spider AV Potamotrygon, Dasyatis spp. Freshwater stingrays Necrosis of bite area, shock, severe pain and oedema No available AV; good wound care Australia Pseudonaja spp. (E) Brown snakes Procoagulant coagulopathy, renal failure, flaccid paralysis2 (rare) CSL brown snake AV or PVAV Notechis spp. (E) Tiger snakes Procoagulant coagulopathy, myolysis, flaccid paralysis2,3, renal failure CSL tiger snake AV or PVAV Oxyuranus spp. (E) Taipans Procoagulant coagulopathy, flaccid paralysis2,3, myolysis, renal failure CSL taipan or PVAV Acanthophis spp. (E) Death adders Flaccid paralysis3 CSL death adder or PVAV Pseudechis spp. Black and mulga snakes Anticoagulant coagulopathy, myolysis, renal failure CSL black snake AV or PVAV Enhydrina schistosa Sea snakes (all species globally) Flaccid paralysis and/or myolysis CSL sea snake AV Atrax, Hadronyche spp. Funnel web spiders Neuroexcitation, shock CSL funnel web spider AV Latrodectus hasseltii Red back spider Neuroexcitation, pain and sweating CSL red back spider AV Chironex fleckeri Box jellyfish Neuroexcitation, cardiotoxicity, local necrosis CSL box jellyfish AV Synanceia spp. Stonefish Severe local pain CSL stonefish AV 1For family name, see Box 8.4. 2Pre-synaptic. 3Post-synaptic. (PVAV = polyvalent antivenom) Copyright © Julian White. A significant proportion of venom is transported from the bite/ sting site via the lymphatic system, particularly for venoms with larger molecular weight toxins, such as many snake venoms. It is recommended that for most forms of envenoming, the patient should be kept still, the bitten limb immobilised with a splint and vital systems supported, where required. A patent upper airway should be specifically ensured and respiratory support provided, if required. For some animals, notably snakes in certain regions, the use of a local pressure pad bandage over the bite site (Myanmar) or a pressure immobilisation bandage (Australia, New Guinea) is recommended. Ineffective or dangerous first aid, such as suction devices, ‘cut and suck’, local chemicals, snake stones (stones of some sort placed over the snakebite) and tourniquets, should not be used. Tourniquets, in particular, have the potential to cause catastrophic distal limb injuries in snakebite when applied too narrowly or too tightly, or left on too long. Transporting patients Where possible, transport should be brought to the patient. It is also vital to obtain medical assessment and intervention at the earliest opportunity, however, so any delay in transporting the patient to a medical facility should be avoided. Severely envenomed patients may develop life-threatening problems, such as shock or respiratory failure, during transport, so ideally the transport method used should allow for management of these problems en route. In resource-poor environments, simple solutions for rapid transport have been successfully employed, such as motorbikes or similar with the patient supported between the driver in front and another person behind the patient. However, this method cannot cope with a patient developing airway compromise or respiratory failure, such as from developing neurotoxicity.

158 • ENVENOMATION dilated pupils, absent reflexes, no withdrawal response to painful stimuli, no movement of limbs, fixed forward gaze with gross ptosis; p. 152) when, in fact, the patient is conscious. Assessment for evidence of envenoming As in other areas of medicine, comprehensive assessment of a patient bitten/stung by a venomous animal requires a good history, a careful targeted examination and, where appropriate, ‘laboratory’ testing (though the latter may just consist of simple bedside tests performed by the doctor; p. 153). Animals that are unlikely to cause serious envenomation in humans should be identified so that inappropriate admission and intervention are avoided. Occasionally, patients may be unaware they have been bitten/stung and thus provide a misleading history. In regions of the world where keeping or handling venomous animals is illegal, patients may be reticent in giving a truthful history. Multiple bites or stings are more likely to cause major envenoming. The following key questions should be asked: • When was the patient exposed to the venomous bite/sting? • Was the organism causing it seen and what did it look like (size, colour)? • What were the circumstances (on land, in water etc.)? • Was there more than one bite/sting? • What first aid was used, when and for how long? • What symptoms has the patient had (local and systemic)? • Are there symptoms suggesting systemic envenoming (paralysis, rhabdomyolysis, coagulopathy etc.)? Assessment and management in hospital On arrival at a health station or hospital, there are two immediate priorities: • identifying and treating any life-threatening problems (e.g. circulatory shock, respiratory failure; see Ch. 16) • determining whether envenoming is present and if that requires urgent treatment. Assessment and management of life-threatening problems Patients who are seriously envenomed must be identified early so that appropriate management is not delayed. Critically ill patients must be resuscitated (p. 202) and this takes precedence over administration of any antivenom. Clinicians should look for signs of: • shock/hypotension • airway and/or respiratory compromise (likely to be secondary to flaccid paralysis) • major bleeding, including internal bleeding (especially intracranial) • impending limb compromise from inappropriate first aid (e.g. a tourniquet) – though beware sudden envenoming on removal of a tourniquet. In a patient with severe neurotoxic flaccid paralysis, who is still able to maintain sufficient respiratory function for survival, clinical assessment may suggest irretrievable brain injury (fixed 8.6 Selected important venomous animals in Africa and Europe Scientific name1 Common name Clinical effects Antivenom/antidote/treatment Africa Naja spp. (E) Cobras Non-spitters Flaccid paralysis3 ± local necrosis/blistering South African PV or Sanofi Pasteur FavAfrica AV Spitters Local necrosis/blistering (flaccid paralysis3 uncommon) South African PV or Sanofi Pasteur FavAfrica AV Dendroaspis spp. (E) Mambas Mamba neurotoxic flaccid paralysis and muscle fasciculation, shock, necrosis (uncommon) South African PV or Sanofi Pasteur FavAfrica AV Hemachatus haemachatus (E) Rinkhals Flaccid paralysis3, local necrosis, shock South African PV Atheris spp. (Vv) Bush vipers Procoagulant coagulopathy, shock, pain and swelling No available AV (can try South African AV) Bitis spp. (Vv) Puff adders etc. Procoagulant coagulopathy, shock, cardiotoxicity, local necrosis/blistering South African PV or Sanofi Pasteur FavAfrica AV Causus spp. (Vv) Night adders Pain and swelling No available AV Echis spp. (Vv) Carpet vipers Procoagulant coagulopathy, shock, renal failure, local necrosis/blistering Specific anti-Echis AV for species/geographical region or Sanofi Pasteur FavAfrica AV Cerastes spp. (Vv) Horned desert vipers Procoagulant coagulopathy, local necrosis, shock Specific or polyspecific AV covering Cerastes from country of origin Dispholidus typus (C) Boomslang Procoagulant coagulopathy, shock Boomslang AV Androctonus spp. North African scorpions Neuroexcitation Specific scorpion AV (Algeria, Tunisia, Sanofi Pasteur Scorpifav) Lelurus quinquestriatus Yellow scorpion Neuroexcitation, shock Specific scorpion AV (Algeria, Tunisia, Sanofi Pasteur Scorpifav) Europe Vipera spp. (Vv) Vipers and adders Shock, local necrosis/blistering, procoagulant coagulopathy (flaccid paralysis2 rare) ViperaTab AV or Zagreb AV or SanofiPasteur Viperfav AV 1For family name, see Box 8.4. 2Pre-synaptic. 3Post-synaptic. More information is available from WHO Guidelines for the prevention and clinical management of snakebite in Africa and from toxinology.com. Copyright © Julian White.

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• Is there any significant past medical history and medication use? • Is there a past exposure to antivenom/venom and allergies? If patients state that they have been bitten by a particular species, ensure this information is accurate. Private keepers of venomous animals may not have accurate knowledge of what they are keeping, and misidentification of a snake, scorpion or spider can have dire consequences if the wrong antivenom is used. An outline of some principal findings on examination of the envenomed patient is shown on page 152. The patient may have a cluster of clinical features suggestive of a particular type of envenoming (see Box 8.1). Even with dangerously venomous animals, some bites/stings will be dry bites and will not require antivenom. The time to onset of first symptoms and signs of envenomation is variable, depending on both animal and patient factors. It may range from a matter of minutes post-bite/sting to 24 hours later in some cases. Therefore, the initial assessment, if normal, must be repeated multiple times during the first 24 hours. Some types of envenomation will not cause symptoms or signs at all, or they may appear very late, long after the optimum time for treatment has passed. Evidence of envenomation may become apparent only through laboratory testing. Laboratory investigations Specific tests for venom are currently commercially available only for Australian snakebites but are likely to be developed for snakebites in other regions. They are not available for other types of envenomation, where venom concentrations are low. For snakebite, a screen for envenoming includes full blood count, coagulation screen, urea and electrolytes, creatinine, CK and electrocardiogram (ECG). Lung function tests, peripheral oximetry or arterial blood gases may be indicated in cases with potential or established respiratory failure. In areas without access to routine laboratory tests, the 20-minute whole-blood clotting test (20WBCT) is useful (p. 153). Treatment Once a diagnosis of likely envenoming has been made, the next and urgent decision is whether to give antivenom. Antivenom may not be the only crucial treatment, however. For a snakebite by a potentially lethal species such as Russell’s viper, the patient might have local effects with oedema, blistering, necrosis, and resultant fluid shifts causing shock, and at the same time have systemic effects such as intractable vomiting, coagulopathy, paralysis and secondary renal failure. Specific treatment with antivenom will be required to reverse the coagulopathy and may prevent worsening of the paralysis and reduce the vomiting, but will not greatly affect the local tissue damage or the renal failure or shock. The latter will require intravenous fluid therapy, possibly respiratory support, renal dialysis and local wound care, perhaps including antibiotics. Each venomous animal will cause a particular pattern of envenomation, requiring a tailored response. Listing all of these is beyond the scope of this chapter (see ‘Further information’ below). Antivenom Antivenom, sometimes inappropriately labelled as ‘anti- snake venom’ (ASV), is the most important tool in treating envenoming. It is made by hyperimmunising an animal, usually horses, to produce antibodies against venom. Once refined, these bind to venom toxins and render them inactive or allow their rapid clearance. Antivenom is available only for certain venomous animals and cannot reverse all types of envenoming. With a few exceptions, it should be given intravenously, with adrenaline (epinephrine) ready in case of anaphylaxis. It should be used only when clearly indicated, and indications will vary between venomous animals (Box 8.7). It is critical that the correct antivenom is used at the appropriate dose. Doses vary widely between antivenoms. In some situations (such as the Indian subcontinent), pre-treatment with subcutaneous adrenaline may reduce the chance of anaphylaxis to antivenom. Antivenom can sometimes reverse post-synaptic neurotoxic paralysis (α-bungarotoxin-like neurotoxins) but will not usually reverse established pre-synaptic paralysis (β-bungarotoxin-like neurotoxins), so should be given before major paralysis has occurred (Fig. 8.2). Coagulopathy is best reversed by antivenom, but even after all venom is neutralised, there may be a delay of hours before normal coagulation is restored. More antivenom should not be given because coagulopathy has failed to normalise fully in the first 1–3 hours (except in very particular circumstances). Thrombocytopenia may persist for days, despite antivenom. The role of antivenom in reversing established rhabdomyolysis and renal failure is uncertain. Antivenom may help limit local tissue effects or injury in the bitten limb but this is quite variable and time-dependent. Neuroexcitatory envenoming can respond very well to antivenom (Australian funnel web spider bites and Mexican, South American and Indian scorpion stings) but there is controversy about the effectiveness of antivenom for some species (some North African and Middle Eastern scorpions). The role of antivenom in limiting local venom effects, including necrosis, is also controversial; it is most likely to be effective when given early. All patients receiving antivenom are at risk of both early and late adverse reactions, including anaphylaxis (early; not always related to immunoglobulin E (IgE)) and serum sickness (late). Non-antivenom treatments Anticholinesterases are used as an adjunctive treatment for post-synaptic paralysis. Prazosin (an α-adrenoceptor antagonist) is used in the management of hypertension or pulmonary oedema in scorpion sting cardiotoxicity, particularly for Indian red scorpion stings, though antivenom is now the preferred treatment. 8.7 Indications for antivenom General indications • Shock/cardiac collapse • Respiratory compromise • Rapidly increasing swelling of the bitten limb • Active bleeding • Intractable non-specific symptoms, including recurrent vomiting Specific indications • Developing paralytic features (ptosis etc.) • Developing rhabdomyolysis • Developing coagulopathy • Developing renal failure • Developing neuroexcitatory envenoming Copyright © Julian White.

160 • ENVENOMATION Follow-up Cases with significant envenomation and those receiving antivenom should be followed up to ensure any complications have resolved and to identify any delayed envenoming. Envenomation by specific animals Venomous snakes Venomous snakes represent the single most important cause of envenomation globally, affecting millions of humans annually and resulting in large numbers of deaths and patients left with long-term disability. Of the 3000-plus snake species, more than 1000 either are venomous or produce oral toxins. The most important venomous snake families are the Viperidae (vipers; includes typical vipers (subfamily Viperinae) and pitvipers, with heat-sensing pit organs (subfamily Crotalinae)) and the Elapidae (cobras, kraits, mambas, coral snakes, sea snakes, Australian snakes). However, there are also dangerous species among the Atractaspididae (side-fanged burrowing vipers of Africa and the Middle East) and the non-frontfanged colubrids (NFFC snakes; several families, including the ‘back-fanged’ boomslang and vine snakes of Africa and the keelbacks of Asia). A selection of important species is included in Boxes 8.4–8.6. Clinical features and management As with other forms of envenoming, the management of snakebite follows the standard assessment guidelines described previously (p. 152). The nature of the risks posed will depend on the specific snake fauna in a given region (p. 153). For example, in the Indian subcontinent, the major snakebite risks are claimed to come from the ‘big four’: cobras, kraits, Russell’s viper and saw-scaled vipers. This list is misleading, though, as it omits other important snakes, including the hump-nosed vipers, king cobra and green pit vipers, all of which can cause severe or lethal envenoming and may not be covered by current Indian antivenoms. Even for those snakes recognised as causing envenoming, there may be major geographical variation in venom and features of envenoming. For Russell’s viper (Daboia spp.), Sri Lankan specimens can cause rhabdomyolysis and flaccid paralysis, in addition to classic severe coagulopathy, haemorrhage, local bite site injury and acute kidney injury (AKI). Indian populations of the same snake are not associated with either rhabdomyolysis or paralysis, but in parts of Southern India may cause anterior pituitary haemorrhage and/or capillary leak syndrome (hypotensive shock plus vascular leakage resulting in pulmonary oedema). Capillary leak syndrome is also encountered with populations of Burmese Russell’s viper (Myanmar), where AKI is especially common and severe. Antivenom raised against venom from one population of these snakes is often poorly effective against bites from snakes from other regions. Similarly, each of the several species of saw-scaled vipers (Echis spp.) spread from West Africa across the Middle East to the Indian subcontinent, including Sri Lanka, has specific venoms that may not be neutralised by antivenoms raised against other species in the genus; Indian antivenoms are ineffective against African species. It follows that, in managing snakebite envenomation, it is critically important to choose the appropriate antivenom and to understand that Antibiotics are not routinely required for most bites/stings, though a few animals, such as some South American pit vipers and stingrays, regularly cause significant wound infection or abscess. Tetanus is a risk in some types of bite or sting, such as snakebite, but intramuscular toxoid should not be given until any coagulopathy is reversed. Mechanical ventilation (p. 202) is vital for established respiratory paralysis that will not reverse with antivenom and may be required for prolonged periods (up to several months in some cases). Fasciotomy as a treatment for potential compartment syndrome or severe limb swelling is an overused and often disastrous surgical intervention in snakebite and is associated with poor functional outcomes. It should be reserved as a treatment of last resort and be used only in cases where compartment syndrome is confirmed by intracompartment pressure measurement and after first trying limb elevation and antivenom, and ensuring that any coagulopathy has resolved. Fig. 8.2 Principal snake venom neurotoxins acting at the neuromuscular junction (NMJ). The pre-synaptic neurotoxins (β-bungarotoxin-like) bind to the cell membrane of the terminal axon (1), form a synaptosome (2) and enter the cell, where they disrupt acetylcholine (ACh) production (3) and damage intracellular structures, including ion channels (4). On initial entry, they cause release of excess ACh, followed by cessation of all ACh release, causing irreversible paralysis until the cell is repaired (days to weeks later). The post-synaptic neurotoxins (α-bungarotoxin-like) bind adjacent to the ACh receptor on the external surface of the muscle end plate and block ACh binding (5), thereby ceasing neurotransmission. Because this action is external to the cell and does not cause cell damage, it is potentially a reversible paralysis. Copyright © Julian White. Motor neuron Acetylcholine Ca2+ Voltage-gated calcium channel Acetylcholine receptor Sodium channels in clefts amplify potential change Depolarisation of muscle membrane β-bungarotoxin class snake neurotoxins Normally, acetylcholine packets are released following calcium influx and cross the NMJ to bind to the ACh receptor α-bungarotoxin class snake neurotoxins

Envenomation by specific animals • 161

Spiders There are vast numbers and great species diversity of spiders, with two broad taxonomic groupings: the more ‘primitive’ Mygalomorphs (several medically important species, especially Australian funnel web spiders (Atrax, Hadronyche and Illawarra)) and the far more diverse Araneomorphs (main clinically important species in the genera Latrodectus (widow spiders), Loxosceles (brown recluse spiders) and Phoneutria (banana or wandering spiders)). Clinical features and management While spiders and spider bites are common, only those genera noted above commonly cause medically significant effects. In most cases this is a neuroexcitatory envenoming, sometimes similar to severe scorpion envenoming (notable from Australian funnel web spiders), but the recluse spiders cause an often painless bite that develops into local skin necrosis and sometimes a systemic illness similar to that caused by the Iranian scorpion, H. lepturus, and with similar lethal potential. For most of these spiders, antivenom remains the key treatment and is life-saving in some cases. Recent studies suggesting that anti-Latrodectus antivenom is ineffective have not been confirmed by independent studies and are in contrast to decades of positive clinical experience. Paralysis ticks Most ticks are vectors for disease but a few species in Australia, North America and parts of Africa can cause flaccid paralysis. Toxins in the saliva act as potent pre-synaptic neurotoxins that can cause gradual-onset ascending flaccid paralysis. There are no antivenoms for tick paralysis. Treatment is based on removal of all ticks and supportive care, including intubation/ ventilation where required. The paralysis usually resolves by about 48 hours following removal of all ticks. Venomous insects A number of insects are venomous but very few cause significant envenoming in humans. Venomous lepidopterans The Lonomia caterpillars of South America, especially Brazil, have numerous protective venomous spines that, on contact with the skin, can discharge a potent procoagulant venom that can cause a progressive and sometimes fatal consumptive coagulopathy, with terminal haemorrhagic and/or organ failure events. Treatment includes use of a Brazilian specific antivenom and supportive care. Venomous hymenopterans Many bees, wasps, hornets and some ants have modified ovipositors in the abdomen that act as stings, attached to venom glands. The quantity of venom injected in a single sting is insufficient to cause significant envenomation, but as many of these venoms are potently allergenic, it can cause severe and sometimes fatal anaphylaxis in sensitised persons (p. 75). Massed stings by hundreds of these insects in a swarm, however, can cause life-threatening systemic envenoming, often with intravascular haemolysis, DIC, shock and multi-organ failure. ‘Africanised’ bees are a particular risk for such attacks in South this may not include every antivenom claiming to cover a given species. It is unwise to assume that everything is known about envenoming by snakes because new clinical information and syndromes are emerging as more detailed studies are carried out. For instance, krait bites (Bungarus spp.), long associated with ‘painless’ bites, later development of devastating flaccid paralysis and a high mortality rate, are now known to have some venom diversity. At least some species can cause rhabdomyolysis and/or severe hyponatraemia, and while bites may be painless, systemic envenomation can cause severe abdominal pain in at least some patients. Among cobra bites, the previous division into ‘non-spitting’, neurotoxic species and ‘spitting’, less neurotoxic species that cause local necrosis is less clear. Non-spitters are now known to spit in parts of their range (e.g. Naja kaouthia in West Bengal) and may cause local necrosis in addition to paralysis. Previously clear diagnostic indicators for envenomation by particular types of snakes, such as Russell’s vipers and saw-scaled vipers causing coagulopathy, have also become less sure, as it is now known that other snakes, such as hump-nosed vipers (Hypnale spp.) and green pit vipers (Trimeresurus spp.), found in similar regions, can also cause marked coagulopathy and yet are often not covered by available antivenoms. The ability to cause life-threatening coagulopathy, associated with snakes previously considered harmless, such as the keelbacks in Asia (Rhabdophis spp.), can further complicate the diagnostic and management process, as antivenom against these snakes is currently available only in Japan. Scorpions Scorpions are second only to snakes in their venomous impact on humankind. Most medically important scorpions are in the family Buthidae and have complex neuroexcitatory venoms with highly specific ion-channel toxins. Classically, stings by these scorpions (some key genera listed in Boxes 8.4–8.6) cause moderate to severe local pain and rapid-onset systemic envenoming with development of a catecholamine storm-like syndrome as the toxins target the nervous system. There may be tachycardia or bradycardia, hyper- or hypotension, profuse sweating, salivation, cardiac dysfunction and pulmonary oedema. Cardiac collapse can occur, especially in children. Other clinical features may vary, depending on the scorpion species. The Iranian scorpion, Hemiscorpius lepturus (principally southwest Iran), causes a quite different presentation, with an initial minor sting, followed by progressive development of bite site or limb necrosis and a potentially lethal systemic envenoming, characterised by intravascular haemolysis, disseminated intravascular coagulation (DIC), secondary renal failure and shock. Clinical features and management The approach to management varies with species and region. In Latin America, specific antivenoms are routinely used and associated with improved outcomes and dramatic falls in mortality rate. In India, the past reliance on prazosin has been replaced with use of specific antivenom, again with improved outcomes. In contrast, in parts of North Africa, past reliance on antivenom has been replaced with use of cardiac support and arguably poorer outcomes. In Iran, H. lepturus stings are treated with antivenom, though as presentation is often delayed because the sting initially appears to be minor, the role of late antivenom is unclear.

162 • ENVENOMATION abdomen or chest are potentially lethal and wounds should be adequately explored, cleaned and allowed to heal by secondary intention. For bites by the blue-ringed octopus and stings by cone snails, rapid-acting venom can cause early cardiovascular collapse and flaccid paralysis. Supportive care is crucial in ensuring survival from these potentially lethal and seemingly trivial local wounds. Sea urchin and venomous starfish wounds can result in multiple penetrating spines, which cause pain and act as a nidus for secondary infection, but surgical removal of spines can be difficult and unrewarding. Further information Books and journal articles Meier J, White J. Handbook of clinical toxicology of animal venoms and poisons. Boca Raton: CRC Press; 1995. World Health Organisation, Regional Office for Africa. Guidelines for the prevention and clinical management of snakebite in Africa; 2010 (afro.who.int). World Health Organisation, Regional Office for South-East Asia. Guidelines for the management of snake-bites; 2010 (searo .who.int). Websites toxinology.com Clinical toxinology guide from the University of Adelaide. America and now in parts of North America. The giant wasps and hornets of Asia can similarly cause systemic envenoming with multiple attacks. Invasive ants, such as Solenopsis spp., are colonising new regions and can cause both allergic reactions and unpleasant local reactions. Marine venomous and poisonous animals The marine environment is dominated by animal life, and many species utilise toxins, either self-produced or taken up from the environment, to arm themselves for either defence or predation. Many of these animals can cause adverse effects in humans, either as a direct venom effect on bites/stings (venomous spiny fish, sea snakes, stingrays, jellyfish, sea urchins, some starfish, cone snails, selected octopuses etc.), or through poisoning if eaten (fugu, ciguatera, scombroid, several types of shellfish poisoning; p. 149). For venomous marine animals, there is antivenom available only for sea snakes, which can cause rhabdomyolysis and/paralytic neurotoxicity; box jellyfish, which can cause very rapid cardiac collapse; and stonefish, which cause intense sting-site pain. In general, marine venoms respond to heat; thus a hot water immersion or shower (about 45°C) is effective at reducing local pain, particularly for jellyfish, stinging fish and stingray stings. For stingray stings, the venom may cause local tissue damage both through sting trauma and a venom effect; wounds penetrating the